Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia (APL), caused by chromosomal rearrangements of the transcription factor RAR (resulting in a fusion protein with the product of other cellular genes, such as PML). Oligomerization of RAR, through a self-association domain present in PML, imposes an altered interaction with transcriptional co-regulators (NCoR/SMRT). NCoR/SMRT are responsible for recruitment of histone deacetylases (HDACs), which is required for transcriptional repression of PML-RAR target genes, and for the transforming potential of the fusion protein. Oligomerization and altered recruitment of HDACs are also responsible for transformation by the fusion protein AML1-ETO, extending these mechanisms to other forms of acute myeloid leukemias (AMLs) and suggesting that HDAC is a common target for myeloid leukemias. Strikingly, AML1-ETO expression blocks retinoic acid (RA) signaling in hematopoietic cells, suggesting that interference with the RA pathway (genetically altered in APL) by HDAC recruitment may be a common theme in AMLs. Treatment of APLs with RA, and of other AMLs with RA plus HDAC inhibitors (HDACi), results in myeloid differentiation. Thus, activation of the RA signaling pathway and inhibition of HDAC activity might represent a general strategy for the differentiation treatment of myeloid leukemias.

Minucci, S., Nervi, C., LO COCO, F., Pelicci, P. (2001). Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias?. ONCOGENE, 20(24), 3110-3115 [10.1038/sj.onc.1204336].

Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias?

LO COCO, FRANCESCO;
2001-05-28

Abstract

Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia (APL), caused by chromosomal rearrangements of the transcription factor RAR (resulting in a fusion protein with the product of other cellular genes, such as PML). Oligomerization of RAR, through a self-association domain present in PML, imposes an altered interaction with transcriptional co-regulators (NCoR/SMRT). NCoR/SMRT are responsible for recruitment of histone deacetylases (HDACs), which is required for transcriptional repression of PML-RAR target genes, and for the transforming potential of the fusion protein. Oligomerization and altered recruitment of HDACs are also responsible for transformation by the fusion protein AML1-ETO, extending these mechanisms to other forms of acute myeloid leukemias (AMLs) and suggesting that HDAC is a common target for myeloid leukemias. Strikingly, AML1-ETO expression blocks retinoic acid (RA) signaling in hematopoietic cells, suggesting that interference with the RA pathway (genetically altered in APL) by HDAC recruitment may be a common theme in AMLs. Treatment of APLs with RA, and of other AMLs with RA plus HDAC inhibitors (HDACi), results in myeloid differentiation. Thus, activation of the RA signaling pathway and inhibition of HDAC activity might represent a general strategy for the differentiation treatment of myeloid leukemias.
28-mag-2001
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/15 - MALATTIE DEL SANGUE
English
Acute Disease; Animals; Cell Differentiation; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Tretinoin
Minucci, S., Nervi, C., LO COCO, F., Pelicci, P. (2001). Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias?. ONCOGENE, 20(24), 3110-3115 [10.1038/sj.onc.1204336].
Minucci, S; Nervi, C; LO COCO, F; Pelicci, P
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/161932
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